Project Summary/Abstract Healthy skeletal muscle slows cognitive decline in Alzheimer’s patients. The 3-fold increase in glucocorticoid production that occurs in Alzheimer’s patients renders their skeletal muscle vulnerable to glucocorticoid- induced myopathy, which is the most common, toxic, non-inflammatory muscle disease in those with elevated glucocorticoids. While this myopathy would decrease muscle health and augment cognitive decline, there are no ways to prevent glucocorticoid myopathy in this population. The inability to treat glucocorticoid myopathy in Alzheimer’s patients limits a clinician’s ability to preserve cognitive function. Despite this issue, our new data show that resistance exercise may be an immediate way for Alzheimer’s patients to blunt the signals that initiate glucocorticoid myopathy. Specifically, our laboratory’s recent publication in healthy muscle shows that a bout of resistance exercise reduces nuclear translocation of the glucocorticoid receptor, a critical step in the process by which glucocorticoids initiate myopathy. The glucocorticoid receptor initiates the myopathy in large part by changing the muscle transcriptome. Accordingly, our new preliminary data show that a bout of resistance exercise will also reverse the glucocorticoid-mediated induction of some glucocorticoid target genes. While promising as a therapy, Alzheimer’s disease induces a novel muscle pathology characterized by accumulation of amyloid-beta plaques that compromises skeletal muscle function, which could render resistance exercise less- or ineffective at mitigating the signals that initiate glucocorticoid myopathy. Therefore, the objective of this proposal is to test whether Alzheimer’s skeletal muscle disease pathology affects the ability of resistance exercise to mitigate the signals that initiate glucocorticoid myopathy. Aim 1 will define the impact of Alzheimer’s muscle disease pathology on the ability of resistance exercise to reduce glucocorticoid receptor activation in the skeletal muscle. Aim 2 will classify and characterize the glucocorticoid target genes in healthy muscle and muscle with Alzheimer’s disease pathology based upon how their hormone-regulated gene expression responds to a bout of resistance exercise. In all, this pilot study will define the extent to which resistance exercise can blunt the signals that initiate glucocorticoid myopathy in the presence of Alzheimer’s muscle pathology. These outcomes are significant because they will provide key information for clinicians to effectively use resistance exercise as part of a comprehensive strategy to prevent glucocorticoid myopathy and preserve cognitive function in the Alzheimer’s population.